Bevacizumab Shows No Improvement in Overall Survival for Patients with Newly Diagnosed Glioblastoma

A recent study showed that patients newly diagnosed with glioblastoma and treated with bevacizumab as part of a first-line therapy that also included the current standard of care did not experience an improvement in overall survival [N Engl J Med. 2014;370:699-708].

Bevacizumab is currently approved for recurrent glioblastoma. It has been speculated that the addition of bevacizumab would enhance the efficacy of the current standard chemoradiotherapy for newly diagnosed glioblastoma and improve patient outcomes. Mark R. Gilbert, MD, MD Anderson Cancer Center, and colleagues collaborated with the Radiation Therapy Oncology Group (RTOG), North Central Cancer Treatment Group, and Eastern Cooperative Oncology Group to conduct a randomized, placebo-controlled, double-blind, phase 3 trial known as RTOG 0825.

Between April 2009 and May 2011, 978 patients were enrolled in the study, of whom 621 were included in the final analysis (309 received placebo; 312 received bevacizumab). The coprimary end points were overall survival and progression-free survival. The researchers used the Kaplan-Meier method to estimate survival distributions and a Cox proportional hazards model to calculate hazard ratios (HRs). At the time of analysis (December 2012), 208 of the 621 patients were alive. Median follow-up time was 20.5 months.

Patients with newly diagnosed glioblastoma were eligible for the study if they were ≥18 years of age, had a Karnofsky performance status of at least 70, and had adequate hematologic, renal, and hepatic function. At baseline, patients underwent neurologic assessment, complete blood counts, blood chemical analyses, and tumor imaging with magnetic resonance imaging or computed tomography.

Either fractionated, conformal, or intensity-modulated radiotherapy (total dose, 60 Gy) and temozolomide were given to patients concomitantly over a period of 6 weeks. Patients were randomly assigned to receive either bevacizumab or placebo administered intravenously (10 mg/kg of body weight) every 2 weeks, starting at week 4 of radiotherapy and continuing until disease progression, severe toxicity, or completion of adjuvant therapy, for a maximum of 24 doses over 12 weeks. Maintenance treatment with temozolomide began 4 weeks after the completion of radiotherapy for 5 consecutive days of a 28-day cycle. If disease progression occurred, patients had the option of being informed about their study group assignment and choosing whether to begin or continue bevacizumab as salvage therapy.

Treatment was halted because of tumor progression or death in 73 of 268 patients given bevacizumab (27.2%) and 135 of 274 (49.3%) in the placebo group. Toxicity or other illness accounted for treatment cessation in 88 patients (32.8%) taking bevacizumab and 45 patients (16.4%) taking placebo. A total of 155 patients in the bevacizumab group discovered their treatment assignment, of whom 39 with disease progression chose to proceed with salvage treatment. In the placebo group, treatment assignment was revealed for 178 patients, and 86 with disease progression chose to begin treatment with bevacizumab.

Results showed median overall survival was 15.7 months for the bevacizumab group and 16.1 months for the placebo group (HR for death in the bevacizumab group, 1.13; 95% CI, 0.93-1.37; P=.21 by log-rank test; Figure). The researchers found tumor progression or death occurred in 512 patients (82.4%). The median duration of progression-free survival was 10.7 months for patients taking bevacizumab and 7.3 months for placebo (HR for progression or death, 0.79; 95% CI, 0.66-0.94; P=.007 by log-rank). The treatment effect for progression-free survival varied over time (P<.001 for proportionality of hazards).

In an interview with First Report Managed Care, Dr. Gilbert observed, “Given the clinical benefit that we saw in patients with recurrent glioblastoma, we were surprised and disappointed by the absence of any survival benefit with frontline use of bevacizumab.”

In a substudy that evaluated the net clinical benefits of treatment (patient-reported outcomes and neurocognitive function), greater deterioration in the group taking bevacizumab was seen, with a decline in neurocognitive function over time. Serious neutropenia and thrombocytopenia were also more common among patients taking bevacizumab compared with patients who took placebo (7.3% vs 3.7%, and 10.2% vs 7.7%, respectively).